ZFN Technology Advances Biopharmaceutical Manufacturing - Pharmaceutical Technology

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ZFN Technology Advances Biopharmaceutical Manufacturing
Applications of ZFN technology in biopharmaceutical cell-line engineering.

Pharmaceutical Technology
Volume 37, Issue 5, pp. 20-23

Improved downstream processing. ZFNs can be used to improve downstream processing by knocking out genes that encode interfering host-cell proteins. If the CHO cell line contains an endogenous protein that copurifies with the r-protein during chromatographic purification, additional and costly steps may be required to remove the endogenous protein. ZFNs can be used to knock out the gene that encodes this endogenous protein. Another potential target may be a protein within the CHO cell that binds the therapeutic r-protein. By knocking out the gene that encodes such a protein, growth and productivity can be improved. The CHO host cell may also produce proteolytic enzymes that could degrade the product before purification. Diminishing protease expression can minimize this effect.

Risk mitigation. The risk of prion or viral infection can be mitigated through genome editing. Retroviral titer in a cell could be reduced by targeting and removing retroviral elements. Additionally, viral uptake pathways can be targeted, conferring resistance to viral attack. Similarly, genes for prion proteins can be targeted and removed.

Combining ZFN modifications. Another benefit of ZFNs is that multiple modifications can be performed in the same clone. Desirable ZFN modifications can be trait stacked into the same cell line, enabling the potential development of a "super" CHO line precisely engineered to efficiently produce safe and effective therapeutic proteins.

Genomic changes improve productivity

Genome editing has vastly improved since the creation of the DUKXB11 cell line. Since 2009, SAFC has applied the ZFN technology to the development of robust CHO cell lines by introducing genomic changes that improve the productivity and processing characteristics of biopharmaceutical manufacturing cell lines. More than 30 specific modifications are available to the biopharmaceutical industry. Through microarray experiments, several key genes that impact cell growth and productivity have been identified and explored.

SAFC has several R&D scientists who identify and validate new genetic alterations that are relevant to the biopharmaceutical industry. They have created the CHOZN GS (GS-/-) and CHOZN DHFR (DHFR -/-) knock-out cell lines. Other available cell lines include knock-outs of GGTA (-/-) and CMAH (-/-), which result in cell lines that produce r-proteins without alpha-gal or Neu5Gc moieties, respectively.

Kate Achtien is an R&D scientist at SAFC,


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